p53 The Gene That Cracked the Cancer Code - Now available

p53 The Gene That Cracked the Cancer Code

Sue Armstrong’s latest book, “p53: the gene that cracked the cancer code”, written with financial support from the Pathological Society, is newly published by Bloomsbury. In this edited extract, Armstrong meets Alfred Knudson, whose ‘two-hit hypothesis’ of tumorigenesis is widely considered one of the most significant theories in modern biology. The extract starts at the point in the late 1980s when researchers have realised that wild type p53 is not an oncogene after all.

For clues to what the true nature of p53 might be we need to rewind the clock to the late 1960s to meet paediatrician and polymath Alfred Knudson, then working at the M D Anderson Cancer Center in Houston, Texas. Here Knudson developed the ‘two-hit’ hypothesis of tumour formation that was to spark a revolution in cancer research. The two-hit hypothesis is such an important concept in the history of p53, and the information about Knudson the man so sparse, that I decided to seek him out myself to hear his story, and flew into Philadelphia where he lives with his wife, Anna Meadows, a paediatric cancer specialist, on a hot July afternoon in 2012.

That first evening, the three of us took a bottle of white wine from the fridge and went out into the warm summer evening for a meal at one of the Knudsons’ favourite Italian restaurants. Next day, Alfred Knudson and I walked together through the city to the College of Physicians, where we sat down to talk in the library. Knudson is now in his 90s, a spare man of medium height with a mop of white hair, deep slow voice like a pint of Guinness and eyes that hold yours unblinking as he speaks.

Born in Los Angeles, California, in 1922, he was the first person in his family to go to university, but felt an academic career was his destiny from his earliest days in high school. Then, he mostly imagined himself as a mathematician or physicist, but the current carried him towards medicine instead. He got a place at the California Institute of Technology where he was required to take courses in chemistry and biology as well as physics and maths and says with a deep chuckle: “I hate to admit how naïve I was, but I came to the conclusion that they already knew everything in physics and it didn’t seem like a very interesting field to get into!” Biology on the other hand excited him with its possibilities, and he decided eventually to study genetics, which seemed to combine biology with his love of maths. Still at Caltech when America entered World War II in December 1941, Knudson was advised that his best hope of staying in school was to join the Forces and apply to study medicine. He accepted a place at Columbia University medical school in New York and, on qualifying, decided to study paediatrics. “Children have some interesting genetic diseases, and I’d had a course in embryology and thought, oh, here’s a great field that is way behind the times – there are all kinds of possibilities with this.”

Knudson’s first serious encounter with childhood cancer came during his residency at New York Hospital, when he was required to spend a month at Sloan Kettering Memorial cancer hospital just across the street. “It had a little unit for children’s cancers. There were about twenty patients there. I had seen a child with Wilms’ tumour before, and somebody with leukaemia – but to see twenty children with cancer just blew me away…”

Knudson re-joined the army for the Korean War, believing they would draft him anyway, but never saw action: he reckoned they had little use for a paediatrician on the frontline. After two years kicking his heels at Fort Raleigh, Kansas, he felt life was passing him by and he was anxious to get back into the world of ideas. He returned to Caltech to do a PhD in genetics and biochemistry in 1953, just months after Crick and Watson had cracked the mystery of DNA’s structure. The Institute, on the crest of the wave of genetic research, was buzzing with intellectual energy.

With his doctorate under his belt, Knudson moved on to the City of Hope Medical Center in Duarte, California, to head up a new paediatric unit with a special focus on cancer. But it was at M D Anderson in Houston, which recruited him ten years later to start a programme in genetics, that he developed his two-hit model of tumour formation. Knudson figured that in order to tease out what was happening at a molecular level in cancer it was best to work with one of the less complicated tumour types. “To start out studying something like polyposis was kind of hopeless, you know?” Polyps, he explained, can eventually turn malignant, but the progression to colon cancer can take years and follow many different paths. “But if a kid can be born with cancer it’s about as simple as it can get. That was my thinking.” Retinoblastoma met this criterion; it was the ideal topic for research.

A rare tumour of the light-detecting cells of the eye, retinoblastoma affects children almost exclusively below the age of five, because it starts in the stem cells of the developing retina that, like the stem cells of all organs of the body, experience an explosion of division and growth during gestation and the early years of life. An early sign of the disease is a milky white appearance to the pupil of the eye. Left undiagnosed and untreated, as it often is in the developing world, it will grow into a grotesque spongy-looking mass that distorts the child’s whole face and will eventually kill.

Knudson did not actually see cases of the disease himself – indeed he had given up treating patients by this stage to concentrate on genetic research – but he struck lucky. He discovered that two people – a paediatrician in England and an ophthalmologist at M D Anderson – had kept detailed records of retinoblastoma cases they had seen. Poring over this rich repository of data, he observed that the disease ran in families as well as occurring sporadically, and that there were distinct differences between the two sorts of patients. Affected children from families with the disease typically developed cancer at a much younger age than those with no family history. And they tended to have multiple tumours in both eyes, while the sporadic form of the disease typically leads to a single tumour in only one eye.

So what did Knudson make of what he was seeing? Something “outrageously brilliant” in its simplicity and far-reaching implications, said Peter Hall (then Professor of Pathology at Queen’s University, Belfast), reviewing the pivotal moments in cancer research nearly four decades later. Here in a nutshell is how Knudson himself explained it to me as we sat together in that quiet library in Philadelphia.

Every gene in the body, except those of the sex cells, ova and sperm, is made up of two copies of itself (or two ‘alleles’), one copy inherited from the father and one from the mother. Knudson realised that in those cases of retinoblastoma with a family history of the disease, the gene responsible was inherited – though in the late 1960s no one was yet able to isolate genes or identify them individually. The overwhelming likelihood, he believed, was that only one copy of the gene, one allele — inherited from either mother or father — would be faulty at birth, and the disease would occur only if and when the other allele developed a fault. His reasoning was confirmed by the fact that among the familial cases, not all the siblings of an affected child developed tumours, though they would all have inherited the same genes from their parents and been similarly susceptible.

In those cases in his data set with no family history of retinoblastoma, faults had obviously developed in both copies of the gene quite by chance over time – explaining why victims tended to be older than those with familial retinoblastoma and typically to have no more than one tumour.

All this suggested to Knudson that one faulty copy of the gene involved in development of the retina is not enough on its own to cause tumour growth at that site. The other copy has to develop a fault also. But — and this was the revolutionary suggestion —until the normal copy too develops a fault, it seems to keep the already-faulty copy in check, so that the cell functions perfectly normally. Only when both copies are faulty do the cells start to behave erratically and to develop into a tumour. Put another way, in all of the cases Knudson observed, something seemed to be breaking down, and the cells involved to be losing their ability to function properly. He proposed that what had happened in these cases was that some kind of brake on proliferation of cells was lost. It was such a simple suggestion, but it swam against the tide of cancer research which, in 1971 when Knudson published his ‘two-hit hypothesis’, was intensely preoccupied with the driving forces of cancer, the newly discovered oncogenes, which implied a gain of function. He was proposing the existence of an equal and opposite force, an ‘anti-oncogene’ (soon to be renamed a ‘tumour suppressor’) — that allows cancer to develop when it is knocked out – implying a loss of function.

Here, the car offers a useful analogy for visualising the forces at work inside cancerous cells, as proposed by Knudson. Think of oncogenes as the accelerator pedals, and tumour suppressors as the brakes: a defective accelerator cable might stick, forcing the car to speed up uncontrollably (a gain of function); brake failure (loss of function) will have a similar effect in that the car won’t be able to stop. But the analogy can be taken still further, since in most cars there are two brake systems. If one system fails, you still have the other, and generally both sets of brakes have to fail for catastrophe to occur. Likewise, for tumour suppressor genes to be involved in cancer it usually requires both copies of the gene, both alleles, to be disabled. This is the central lesson of retinoblastoma, and the essence of Knudson’s ‘two-hit hypothesis’.

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“There is a war on to rid the human race of cancer and this is a story from the front line. By interviewing the individual scientists, attending their intense conferences and understanding the complex language of cutting edge science, Sue Armstrong has been able to tell the story of this amazing journey of discovery in a way that fascinates and inspires but is still accessible,” Sir David Lane

“Sue Armstrong tells a fascinating story of human ingenuity at its best. It is a triumphant account of fundamental scientific discoveries that solve deep mysteries about life and death in cells and genes, but along the way she gives us a very human narrative, full of serendipity, rivalry, obstinacy, coincidence, courage and determination,” Matt Ridley, author of Genome.

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